Depression is a highly prevalent in Parkinson's disease (PD) and is often said to contribute more to the lowered quaUty of life than the debilitating motor symptoms. Although the etiology of depression in PD is unknown, understanding the potential pathophysiological processes and deleterious consequences of these co-morbidities is of high importance, and may lead to the development of novel treatment therapies. Currently, models aimed at deciphering the complex neurobiological interactions of PD and depression are lacking. In the proposed studies, we will combine the intrastriatal 6-hydroxydopamine rat model of PD with a widely accepted rat model of stress-induced depression symptomology (chronic variable stress model), to test the hypothesis that experimental depression exacerbates the neurodegeneration and associated dysfunction of the injured nigrostriatal dopaminergic system via deleterious glucocorticoid mechanisms as evaluated by functional, morphological, neurochemical, and gene expression analyses. To test potential mechanisms by which depression may increase nigrostriatal vulnerability, SPECIFIC AIM #1 will evaluate the necessity and sufficiency of glucocorticoids in dopaminergic degeneration and motor dysfimction, and determine plausible molecular correlates contributing to the enhanced degeneration. In the context of the dopaminergic mesotelencephalic system, these aims will be addressed by using forelimb-use asymmetry behavioral tests, tyrosine hydroxylase immimohistochemistry, unbiased stereology, HPLC analysis of dopamine and its metabolites, and custom PCR arrays. The overall goal of this project is to gain functional, morphological and mechanistic insight into the co-morbidity of PD, stress and depression. Moreover, this research may lead to future therapies that ameliorate alTective as well as motor symptoms of PD. RELEVANCE (See instmctions): Almost half of all patients with Parkinson's disease experience coexisting major depression. The present research will investigate whether having abnormal levels of stress hormones is a mechanism by which depression worsens motor symptoms and accelerates nerve cell death in PD. This work will help us understand the underlying mechanisms interacting in these two co-morbid disorders and may reveal novel therapeutic approaches to relieve both mood and motor symptoms of PD.